Project Summary: Urinary tract infection (UTI) is the most common serious bacterial infection in childhood, affecting approximately 3% of all children by six years of age. The current standard of care for young children who present with UTI is to perform a voiding cystourethrogram (VCUG) to evaluate for the presence of vesicoureteral reflux (VUR), a condition that is present in approximately 30-40% of children with UTI and is thought to increase the risk of renal scarring. Traditionally, children with VUR identified on VCUG are treated with daily prophylactic antibiotics until the VUR resolves, or have surgical correction of the VUR. Recently the role of VUR in contributing to renal scarring and the utility of VCUG, prophylactic antibiotics and VUR surgery have been questioned. Concerns have also been raised about the cost and potential harms of VCUGs and daily prophylactic antibiotics. In this U01 application we propose a multi-center, centrally randomized, double-blind, placebo-controlled, equivalence trial to determine whether, in the setting of prompt recognition of UTI symptoms and early treatment of confirmed UTI, prophylactic antibiotics are better than placebo in reducing renal scarring;and whether DMSA evidence of renal scarring or pyelonephritis at presentation of UTI modifies the effect of prophylactic antibiotics. We will also determine whether antibiotic prophylaxis increases the rate of gastrointestinal (Gl) colonization with antibiotic resistant E.coli and Klebsiella spp. and Gl colonization with Pseudomonas spp. Recognizing that the protocols implemented by the Clinical Trial Centers (CTCs) selected for this U01 will be developed by concensus [sic], this application also describes the strengths that the Children's Hospital of Philadelphia (CHOP) brings as a potential CTC in the NIDDK's Clinical Study of Vesicoureteral Reflux. These include (1) content area expertise and experience recruiting and retaining patients in large clinical studies, (2) a vast pediatric healthcare network of primary care and urology practices from which to recruit patients, (3) a network-wide state-of-the-art searchable electronic medical record and billing system suitable for identifying potential participants, and (4) an institutional commitment to and infrastructure for conducting the highest quality clinical research. Relevance: The trial has the potential to substantially impact the diagnostic work-up and management for the tens of thousands of children in the US who develop UTIs each year